APPENDIX 2:
Dependence on & Withdrawal from Paxil
From the mid-1980s, in the course of their development work with Paxil,
Beecham Pharmaceuticals/SmithKline Beecham noted the occurrence ofproblems on withdrawal from this drug. By the mid-1980s, the company wasaware of these problems, having been informed of the problem by senior
figures in the field and having undertaken their own healthy volunteer trials.
For example, Professor Peter Tyrer, current editor of the British Journal of
Psychiatry, and head of department in University College London, and aclinical triallist for SmithKline Beecham in the early 1980s, reported to thecompany that treatment with Paxil seemed to entail a significant risk ofdependence. The following is from a broadcast interview from October 2004
with Professor Tyrer on BBC’s Panorama program:
PT: After the trial ended they said, ‘can we continue on these tablets
because we feel we’ve got to have them because they seem to be soeffective’, but more concerning.. what was of more concern to us was the factthat they were saying, ‘I cannot tolerate the symptoms when I stop it’.
SJ: As far as you were concerned then, were these people dependent on
Seroxat? [The British trade name for Paxil]
PT:

They were showing, yes, signs of dependence......after only 6 weeks.

SJ:

Some of the withdrawal effects were very disturbing.

PT: They also felt more anxious, they felt this feeling of dysphoria, thefeeling of being depressed, and in some cases entertaining suicidal
thoughts… Yes, it is serious … we were led to believe that these drugs wereparticularly effective against suicidal thoughts, and therefore having them atany stage during the course of treatment even.. .and on withdrawal, was amatter of great concern.
SJ: Professor Tyrer didn’t investigate these problems any further at the time,
but he did tell GlaxoSmithKline what he’d found. He says they weren’t very
interested.
PT: It was very.. um.. important to concentrate on the positive, so we didn’t
expect that they would rush in and investigate this problem as a matter ofpriority.
SJ:

And as far as you’re aware they didn’t investigate the problem?

PT:

No.

SJ: We asked GlaxoSmithKline if further studies were commissioned as aresult of Professor Tyrer’s findings on withdrawal. They didn’t say. What they1

did tell us was the company “reviewed reports of such symptoms in all its
clinical trials as a matter of course”.
SmithKline Beecham had already run a set of healthy volunteer studies, which
involved exposing normals to drug treatment for only two to three weeks, inwhich the protocol monitored symptoms of withdrawal for a week afterwards,
although GlaxoSmithKline deny that studies designed to detect withdrawal
were ever conducted. Approximately 65% of healthy volunteers exposed for
only 2-3 weeks reported problems consistent with dependence andwithdrawal, during the week of observation following the study. The
commonest symptoms experienced were of depression and anxiety as well asa range of other phenomena such as nightmares, dizziness and problems thatwere coded under non-specific headings such as asthenia and malaise.
These are symptoms indicative of physical dependence on the drug – they
overlap heavily with the symptoms produced by benzodiazepine withdrawal
for instance. Finally in terms of severity, there are grounds for concern in thatthe problems on withdrawal recorded in healthy volunteers exposed for only
two to three weeks included a suicide.
Despite this evidence when Paxil came on the market in both America andBritain, the warnings about possible withdrawal problems were extremely
misleading. For instance in the United Kingdom: “As with any psychiatric
medication, it is advisable to discontinue therapy gradually as abrupt or
sudden discontinuation may lead to symptoms such as disturbed sleep,
irritability or dizziness”1. In the United States, prior to 12/14/01, the only
reference to withdrawal in the Paxil label was under postmarketing reports,
which lists voluntary reports of adverse events in patients that “may have nocausal relationship with the drug”. The label further states that “There havebeen spontaneous reports that discontinuation (particularly when abrupt) may
lead to symptoms such as dizziness, sensory disturbances, agitation oranxiety, nausea and sweating: these events are generally self-limiting”.
These statements need to be read in historical context. In 1991, when Paxil
was launched clinicians were actively switching patients frombenzodiazepines to SSRIs and one of the primary reasons they offered wasthat unlike the benzodiazepines, antidepressants in general, including SSRIs,
were not addictive or dependence producing. Indeed in what looks like aclear effort to move into the anxiety marketplace, where benzodiazepines had
been heavily used, GlaxoSmithKline pursued a policy of profiling Paxil as the
anxiolytic antidepressant, and this can only have compounded problems forthis group of patients.
Unless, they were more wary or skeptical than the average, primary care
physicians and psychiatrists will have confidently brushed off patient concernson this point, as I and others did at the same time.
Furthermore, despite evidence of the emergence of depressive and anxiety
symptoms in healthy volunteers on withdrawal, the SSRI companies were
1 1990/1991 Datasheet Compendium for Paxil.

2very actively pursuing prophylactic studies in the late 1980s and early 1990sin depressed patients who had apparently responded to treatment. This
involved clinical trials in which patients who had previously responded to Paxil
or Zoloft were re-randomized to ongoing Paxil or placebo. A model was being
created and actively marketed that depression was a chronic condition thatmight need long-term or even lifelong treatment. Against this background theemergence of symptoms on withdrawal was increasingly likely to beinterpreted by GPs and others as evidence of a returning illness.
It is clear now that SmithKline Beecham must have known that a certain
proportion of these patients re-randomized to placebo, who subsequently
complained of depressive and anxiety symptoms, were suffering fromwithdrawal problems. These withdrawal problems however appear to havebeen used as a basis for claiming that continued SSRI intake had aprophylactic effect against nervous and depressive problems. Based on thisSmithKline sought and have received licenses to make these claims regarding
prophylaxis for Paxil.
This has had a very clear consequence for clinical practice. When patients
have tried to discontinue treatment, they have commonly found their physician
claiming that the symptoms they have had are evidence not of a withdrawal
syndrome but of a need to continue with treatment indefinitely, potentially for a
lifetime.
Thus there appears to have been a failure by companies to seek and inform
regulators of possible problems, and a failure by regulators. Whether the
regulatory failure is a simple clinical one of failing to appreciate the possibilityof hazards or has involved a more active involvement with companies to bury
evidence of problems, as happened in the case of Prozac, Paxil and Zoloft
and the risk of suicide these drugs pose, remains to be established publicly.
Whatever the origins of the failure to accurately delineate the problem at the
point of initial marketing, the background data, reports from senior clinicians
and the outcomes of healthy volunteer studies that point clearly to a problem
makes the reports of withdrawal following the marketing of Paxil lesssurprising than might otherwise have been the case.
From shortly after the licensing of this drug regulators and journals were
flooded with reports of withdrawal problems for Paxil. There was anincreasing series of articles in the scientific literature2, and Paxil featured
prominently in this literature3. These reports featured the words withdrawal
2 Medawar C (1997). The Antidepressant Web. Int J Risk & Safety in Medicine 10, 75-126.
3 Arya DK (1996). Withdrawal after discontinuation of Paroxetine. Aust N Z J Psychiatry, 30(5), 702; Ayd F (1994). Paroxetine withdrawal symptoms. Int Drug Ther
Newsl. 29:36; Barr L, Goodman W, Price LH (1994). Physical symptoms associated with paroxetine discontinuation. Am J Psychiatry 151, 289; Bloch M, Stager S, Braun A,
Rubinow D (1995). Severe psychiatric symptoms associated with paroxetine withdrawal. Lancet. 346, 57; CSM/MCA, Current Problems in Pharmacovigilance, Volume 19,
February 1993 “Dystonia and withdrawal symptoms with paroxetine (Seroxat),; Dahl M,. Olhager E, Ahlner J (1997). Paroxetine withdrawal syndrome in a neonate. Br J
Psychiatry. 171, 391-2; D’Arcy (1993). Dystonia and withdrawal symptoms with paroxetine. International Pharmacology Journal, 7:140; Dominguez RA,. Goodnick P(1995). Adverse events after the abrupt discontinuation of paroxetine. Pharmacotherapy. 15, 778-80; Brauer L, Rukstalis M, De Wit H (1995). Acute subjective responses toparoxetine in normal volunteers. Drug Alcohol Depend. 39, 223-30; Fava M (1998). A comparison of symptoms following treatment interruption: Evidence from arandomized, double-blind trial with fluoxetine, sertraline, and paroxetine. Eur Psychiatry 13(suppl 4), 204-205; Fava GA, Grandi S (1995). Withdrawal syndromes after3

and dependence prominently4. In the mid-1990s, a number of reviews
focused attention specifically on the role of the serotonergic system inwithdrawal5.
It is now clear that the rates at which withdrawal problems have been reported
to regulators on this drug exceed the rates at which withdrawal problems havebeen reported on any other psychotropic drug ever. The Paxil rates greatly
exceed rates at which comparable problems were reported for the
benzodiazepines. The rate at which problems have been reported in the UK,
appears to hold in countries other than the UK also, with the World HealthOrganization recording a higher rate of reports for both withdrawal problems
and dependence on Paxil than for the benzodiazepines (see Tables 1 & 2).
A review of the UK regulators ADROIT database obtained in July 2002 showsthat SSRIs and similar antidepressants account for five of the top six drugs forwhich such reactions have been reported:

paroxetine and sertraline discontinuation. J Clin Psychopharmacol.15, 374-5; Judge R, Parry MG, Quail D, Jacobson J (2002). Discontinuation symptoms: comparison ofbrief interruption in fluoxetine and paroxetine treatment. Int Clin Psychopharmacol. 17, 217-25; Keuthen N, Cyr P, Ricciardi JA, Minichiello W, Buttolph M, Jenike M(1994). Medication withdrawal symptoms in obsessive-compulsive disorder patients treated with paroxetine J Clin Psychopharmacol 14, 206-7; Landry P, Roy L (1997).
Withdrawal hypomania associated with paroxetine. J Clin Psychopharmacology 17, 60-1; Lane R (1996). Withdrawal symptoms after discontinuation of selective serotonin
reuptake inhibitors (SSRIs). J Serotonin Research 3,75-83; Milliken C, Cooper SJ (1998). Withdrawal Symptoms from Paroxetine. Human Psychopharmacology 13, 217-9;
Pacheco L, Malo P, Aragues E, Etxebeste M (1996). More cases of paroxetine withdrawal syndrome. Br J Psychiatry 169, 384; Phillips SD (1995). A possible paroxetine
withdrawal syndrome. Am J Psychiatry 152(4):645-6; Price JS, Waller PC, Wood SM, MacKay AV (1996). A comparison of the post-marketing safety of four selective
serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal. Br J Clin Pharmacol. 42, 757-63; Pyke RE (1995). Paroxetine withdrawal
syndrome. Am J Psychiatry 152, 149-50; Reeves R, Pinkofsky H (1996). L’hermitte's sign in paroxetine withdrawal. J Clin Psychopharmacol, 16, 411-2; Rosenbaum JF, Fava
M, Hoog SL, Ascroft RC, Krebs WB (1998). Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 44, 77-87;
Shoenberger D (2002). Discontinuing paroxetine: a personal account. Psychother Psychosom. 71, 237-8; Strickland G, Hough D (2000). Unilateral facial numbness andvisual blurring associated with paroxetine discontinuation. J Clin Psychopharmacol. 20, 271-2.
4 Arya DK (1996). Withdrawal after discontinuation of Paroxetine. Aust N Z J Psychiatry, 30(5), 702; Ayd F (1994). Paroxetine withdrawal symptoms. Int Drug Ther
Newsl. 29:36; Bloch M, Stager S, Braun A, Rubinow D (1995). Severe psychiatric symptoms associated with paroxetine withdrawal. Lancet. 346, 57; CSM/MCA, Current
Problems in Pharmacovigilance, Volume 19, February 1993 “Dystonia and withdrawal symptoms with paroxetine (Seroxat),; Dahl M,. Olhager E, Ahlner J (1997).
Paroxetine withdrawal syndrome in a neonate. Br J Psychiatry. 171, 391-2; D’Arcy (1993). Dystonia and withdrawal symptoms with paroxetine. International
Pharmacology Journal, 7:140; Fava GA, Grandi S (1995). Withdrawal syndromes after paroxetine and sertraline discontinuation. J Clin Psychopharmacol.15, 374-5;
Keuthen N, Cyr P, Ricciardi JA, Minichiello W, Buttolph M, Jenike M (1994). Medication withdrawal symptoms in obsessive-compulsive disorder patients treated withparoxetine J Clin Psychopharmacol 14, 206-7; Landry P, Roy L (1997). Withdrawal hypomania associated with paroxetine. J Clin Psychopharmacology 17, 60-1; Lane R(1996). Withdrawal symptoms after discontinuation of selective serotonin reuptake inhibitors (SSRIs). J Serotonin Research 3,75-83; Milliken C, Cooper SJ (1998).
Withdrawal Symptoms from Paroxetine. Human Psychopharmacology 13, 217-9; Pacheco L, Malo P, Aragues E, Etxebeste M (1996). More cases of paroxetine withdrawal
syndrome. Br J Psychiatry 169, 384; Phillips SD (1995). A possible paroxetine withdrawal syndrome. Am J Psychiatry 152(4):645-6; Price JS, Waller PC, Wood SM, MacKay
AV (1996). A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal.
Br J Clin Pharmacol. 42, 757-63; Pyke RE (1995). Paroxetine withdrawal syndrome. Am J Psychiatry 152, 149-50; Reeves R, Pinkofsky H (1996). L’hermitte's sign inparoxetine withdrawal. J Clin Psychopharmacol, 16, 411-2
5 Coupland NJ, Bell CJ, Potokar JP (1996). Serotonin reuptake inhibitor withdrawal. Journal of Clinical Psychopharmacology 16, 356-362. Berber MJ (1998). FINISH:
remembering the discontinuation syndrome. Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, and Hyperarousal (anxiety/agitation) J Clin
Psychiatry 59, 255; Black K, Shea C, Dursun S, Kutcher S(2000). Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatry
Neurosci 25, 255-256; Donoghue J, Haddad P (1999) Pharmacists lack knowledge of antidepressant discontinuation symptoms. J Clin Psychiatry 60, 124-125; Drugs andTherapeutics Bulletin (1999). Withdrawing patients from antidepressants. 37, 49-52; Fava G (1995). Holding on: depression, sensitization by antidepressant drugs, and the
prodigal experts. Psychother Psychosom. 64, 57-61; Frost L, Lal S (1995). Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors. Am J
Psychiatry 152, 810; Haddad P, Lejoyeux M, Young A (1998). Antidepressant discontinuation reactions. BMJ. 316, 1105-6; Haddad P (2001). Antidepressant discontinuation
syndromes. Drug Safety 24, 183-97; Haddad P (1999). Do antidepressants have any potential to cause addiction? J Psychopharmacology 13, 300-7; Haddad P, Qureshi M(2000). Misdiagnosis of antidepressant discontinuation symptoms. Acta Psychiatr Scand 102, 466-7; Lejoyeux M, Ades J, Mourad I, Solomon J, Dilsaver S (1996)
Antidepressant Withdrawal Syndrome: Recognition, Prevention and Management. CNS Drugs 5, 278-92; Mallya G, White K, Gunderson C (1993). Is there a serotonergic
withdrawal syndrome? Biol Psychiatry.33, 851-2

4

It is clear from these bodies of data that SSRIs are linked to withdrawal
problems, and that Paxil is linked to more reports of withdrawal than any otherdrug in clinical history. The frequency of reporting gives some measure of
the severity of many of these withdrawal syndromes. Reporting would not belikely in the event of less severe clinical problems. It must also be
remembered that this reporting has taken place in the face of a de facto
company denial that there could be any serious problem here, and active
company research aimed at portraying any problems as the re-emergence ofa depressive illness.
TABLE 1DRUG
PAROXETINE – SSRI
VENLAFAXINE – SSRI
TRAMADOL – Opioid
FLUOXETINE – SSRISERTRALINE – SSRICITALOPRAM – SSRIZOPICLONE – Benzodiazepine
LORAZEPAM – Benzodiazepine
FENFLURAMINEDIAZEPAM – Benzodiazepine
NITRAZEPAM- Benzodiazepine
BUPRENORPHINE – Opioid
BUPROPION
CIMETIDINE
CLOMIPRAMINEAMITRIPTYLINEBACLOFENTRIFLUOPERAZINECLOZAPINEFLUVOXAMINEMIRTAZAPINE

Number of UK reports ofWithdrawal reactions
1281
272
117
91
81
49
44
38
28
24
21
19
18
18
18
15
15
14
13
13
13

5

Comparable data are on file with the WHO.
TABLE 2DRUG
WHO Withdrawal reactions
PAROXETINE – SSRI
2003
VENLAFAXINE – SSRI
1058
ALPRAZOLAM –843
Benzodiazepine
SERTRALINE – SSRI
585
FENFLURAMINE450FLUOXETINE – SSRI
402
TRAMADOL – Opioid
389
PHENTERMINE
371
LORAZEPAM – Benzodiazepine
282
DIAZEPAM – Benzodiazepine
192
TRIAZOLAM – Benzodiazepine
188
The clinical literature on patients going into withdrawal on SSRIs has givenrise to an awareness of a range of novel phenomena, which have variously
been described as electric head or electric shock like sensations8. The
discomfort posed by these and other problems has been extreme so that thepatient literature is now replete with accounts of patients presenting
themselves to the emergency departments of hospitals suspecting illnesses
from strokes through to heart attacks. An indeterminately large number ofpatients have been investigated in hospital for problems, which may well havebeen withdrawal related problems. A large number of such patients will havebeen treated inappropriately for other problems following a mistaken
diagnosis made in good faith by physicians unaware of the possibility of Paxil
related withdrawal problems.
Based on healthy volunteer and clinical studies, the frequency with whichthese problems may be happening is a matter for concern. The RCTs
undertaken in patients were not designed to pick up problems on withdrawal –unlike the healthy volunteer studies on Paxil for instance which were aimed at
detecting problems. In healthy volunteer studies approximately 65% ofsubjects had some features of withdrawal on discontinuing Paxil. The RCT
evidence from patients can best be re-interpreted in the light of these findings
as evidence that approximately 25% of patients taking Paxil will havesufficiently severe problems that they will be unable to discontinue without ataper requiring several months of treatment possibly supplemented bysubstitution of other agents.

6 Trenque T, Piednoir D, Frances C, Millart H, Germain ML (2002). Reports of withdrawal syndrome with the use of SSRIs: a case/non case study in the French
pharmacovigilance database. Pharmacoepidemiology and Drug Safety 11, 281-283.
7 Dallaire S (2003). Withdrawal reactions with paroxetine and other SSRIs. Canadian Adverse Reaction Newsletter 13, issue 2.
8 Medawar C, Herxheimer A, Bell A, Jofre S (2002). Paroxetine, Panorama and user reporting of ADRs: Consumer intelligence matters in clinical practice and postmarketing drug surveillance. Int J Risk & Safety in Medicine 15, 161-169.

6

In a proportion of patients who are able to discontinue by taper, ongoingproblems in many cases of very significant severity can be expected tocontinue for months or even longer. In my clinical experience, a proportion ofcases, perhaps as high as 5-10%, patients on Paxil will be unable todiscontinue by any means.
In the case of patients who cannot discontinue, there are very real problems
to be faced. SSRIs emotionally blunt people9. If an individual who is unable
to stop treatment is one who suffers clear emotional blunting on the drug,
such a patient would be therefore condemned to a life in which they will be
unable properly to appreciate a range of things from music or other works ofart to a range of important emotional experiences.
This can be illustrated by the sexual difficulties such patients face. One of theconsequences of Paxil intake that has been linked to its capacity to cause
emotional blunting is sexual dysfunction. In both men and women, this drug
delays or inhibits the capacity to have an orgasm. Patients unable todiscontinue treatment are thereby locked into a permanent sexual dysfunction.
SSRIs have also been associated with a range of problems from brain cellloss in animal models10 through to gastrointestinal hemorrhage11, uterine
hemorrhage12, cerebral hemorrhage13 and cardiac problems in humans.
Aside from the enduring risks ongoing treatment poses, the severity of theanxiety that withdrawal engenders can be extreme. The data from the 30days post taper phase in Paxil RCTs shown in Tables 4 & 514:
Table 4: Incidence of possibly suicide-related events:
all placebo controlled trials 30 days post-taper
Paxil
PlaceboOdds Ratio%%
Overall
33/92198/64552.90
0.36%
0.124%
Depression
22/3769
3/2402
4.67
0.584%
0.125%
Non-Depression
11/5450
5/40531.63
0.201%
0.123%
Table 5 Incidence of suicide-related & hostility events: all placebo
controlled trials 30 days post-taper
Paxil

PlaceboOdds Ratio

9 For a good account of this see Walsh H (2003). Touching the Void, Guardian Thursday June 12th.
10 Kalia M, O’Callaghan JP, Miller DB, Kramer M (2000). Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology ofserotonergic nerve terminals using serotonin immunohistochemistry. Brain Research 858, 92–105.
11 Oksberg-Dalton S et al (2003). SSRI-Related Increases in GI Bleeding Risk Greatly Potentiated With NSAID Use. Arch Intern Med 163,59-64.
12 Meijer. Archives of Internal Medicine
13 Singhal A et al (2002). Cerebral Vasoconstriction and Stroke After Use of Serotonergic Drugs. Neurology 58, 130.
14 Data from Glaxo SmithKline Archives, and from CSM Expert Working Group on Safety of SSRIs

7

%%Overall
43/92198/64550.466%
0.138%
Depression
24/3769*
3/2402
0.637%
0.142%
Non-Depression
19/5450
5/40530.349%
0.135%* Plus one pediatric hostility event in 30 days post taper.

3.38
4.45
2.56

This is a rate of 3 suicide related or hostility events per thousand. The true
figure is likely to be higher as events in the 30 post taper phase were notrecorded as well in early trials. It is also the case that events in real life may
be quite a bit higher than this as subjects are stopped or stop abruptly from a
20 mg dose or higher, because no-one has warned them about the potentiallylethal risks from withdrawal. It is of some interest that these events occur inboth depression and non-depression trials and therefore cannot be put down
to any one disorder. The data from trials where Paxil is compared to otheragents shows that it causes more of a problem than other drugs.
The company response to this clinical problem from 1997 through to 2004
was to campaign aggressively on a number of fronts. These involved
claiming any problems were common to all SSRIs, were mild in any event andself-limiting and that the short half life of Paxil provided advantages comparedto other drugs like Prozac. The campaign involved rolling out a series ofarticles by opinion leaders emphasizing that the withdrawal issues were of noconcern to clinicians and that it would be a much greater evil to leave patients
untreated.
It was not until 2004 GlaxoSmithKline changed their product information under
the heading of adverse events from pediatric clinical trials to state that:In studies that used a tapered withdrawal regimen, symptoms reported
during the taper phase or upon discontinuation of paroxetine at a frequency ofat least 2% of patients and that occurred at a rate of at least twice that ofplacebo were: nervousness, dizziness, nausea, emotional lability (including
crying, mood fluctuations, self-harm, suicidal thoughts, and attempted suicide)
and abdominal pain.
This statement is consistent with the data from adult populations andindicative of the severity of the problems. The data make it clear that astatement comparable to this should be present on the labeling for adults also.
It should be noted that a great deal of the data underpinning the increased
risk of suicidal acts during the withdrawal phase, in table form above, wasgenerated in the 1980s and early 1990s.

8